TLR2とTLR4が共有するシグナリングカスケードの活性化におけるTIRAPの重要な役割
Masahiro Yamamoto1, Shintaro Sato, Hiroaki Hemmi
1Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Japan Science and Technology Corporation, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Nature
|November 26, 2002
まとめ
Toll-like receptor (TLR) シグナリングアダプタ TIRAP (Toll-interleukin-1受容体ドメインを含むアダプタタンパク質) は,TLR2およびTLR4のシグナリングにおけるMyD88依存経路にとって,MyD88独立経路には欠かせない.
科学分野:
- 免疫学 免疫学とは
- 分子生物学は分子生物学である.
- 細胞シグナル伝達 細胞信号伝達
背景:
- トール型受容体 (TLR) は,そのトール/インタールイキン-1受容体 (TIR) ドメインを通じて免疫反応を媒介する.
- MyD88はTLRシグナル伝達における一般的なアダプタータンパク質ですが,一部のLPS応答は,その欠如に耐えられます.
- TIRAP (Mal) は,MyD88から独立したTLR4信号伝達を媒介すると仮定された.
研究 の 目的:
- TLR信号伝達経路におけるTIRAPの役割を調査する.
- TIRAPがMyD88独立反応に関与するかどうかを判断する.
- TIRAPを利用する特定のTLRとシグナル伝達経路を明確にする.
主な方法:
- TIRAP欠乏マウスにおけるLPS誘発反応の分析.
- スプレノサイト増殖とサイトカイン生成の評価.
- NF-kappaBとMAPKの活性化運動を評価する.
- インターフェロン誘導性遺伝子発現と dendritic 細胞の成熟の検討.
- 様々なTLRアゴニスト (TLR2,TLR3,TLR7,TLR9) に対する反応を検査する.
主要な成果:
- LPS誘発のスプレノサイト増殖とサイトカイン生成は,TIRAP欠乏したマウスでは廃止された.
- NF-kappaBとMAPKの活性化により,TIRAP欠乏マウスでは,MyD88欠乏マウスと同様の運動が遅れたことが示されました.
- インターフェロン誘導性遺伝子発現とデンドリット細胞の成熟は,TIRAP欠乏したマウスでは普通に発生しました.
- TIRAP欠乏マウスは,TLR2リガンドに対して欠陥反応を示したが,TLR3,TLR7またはTLR9アゴニストに対して欠陥反応を示さなかった.
- TIRAPは,TLR2とTLR4に共通するMyD88に依存したシグナル伝達経路に不可欠です.
結論:
- TIRAPはTLR4信号に特異的ではない.
- TIRAPは,MyD88から独立したTLRシグナリングを仲介するものではありません.
- TIRAPは,TLR2およびTLR4の活性化のためのMyD88に依存した経路において重要な役割を果たしています.
関連する概念動画
Tail-anchoring of Proteins in the ER Membrane
Tail-anchored, or TA, proteins are estimated to make up to 3-5% of membrane proteins found in the eukaryotic cell. Such proteins have a single transmembrane domain located approximately 30 amino acid residues upstream from the C-terminal end. As a result, the signal recognition particle (SRP) cannot guide a TA protein to the ER membrane for cotranslational insertion. Hence, they are integrated into the ER membrane post-translationally using their C-terminal end as the anchor. TA proteins...
Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Receptor Tyrosine Kinases
Receptor tyrosine kinases or RTKs are membrane-bound receptors that phosphorylate specific tyrosine on protein substrates. RTKs regulate cellular growth, differentiation, survival, and migration. They contain an extracellular ligand binding domain, a transmembrane domain, and a cytosolic tail with intrinsic kinase activity. Several extracellular signaling molecules activate RTKs in one or more ways and relay the signal downstream. Ligands such as platelet-derived growth factor (PDGF) or...
MAPK Signaling Cascades
Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
IP3/DAG Signaling Pathway
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
T Cell Activation and Clonal Selection
T cells are integral to our adaptive immune system, recognizing and effectively responding to foreign antigens. T cell activation and clonal selection are pivotal in orchestrating this immune response. This article elucidates these mechanisms, detailing the roles of cluster of differentiation (CD) markers, major histocompatibility complex (MHC) molecules, costimulatory signals, and the process of clonal selection.
Naive T cells that have not yet encountered an antigen express two primary CD...
Naive T cells that have not yet encountered an antigen express two primary CD...


